The development of an HIV vaccine has been slow, and successes in various models including human trials have been limited. A candidate vaccine that can induce broadly neutralizing antibodies, systemic Th1 and CTL responses as well as mucosal IgA and CTL responses, represents a logical and required developmental strategy. Our preliminary data generated in various mouse models and in primates suggest that certain bacterial DNA sequences (ISS or CpG motif) provide the necessary adjuvanticity and immunomodulatory properties to address this requirement. Hence, ISS-based vaccines (conjugated or co-injected with an antigen) can generate a state of "global immunity"; i.e., humoral and cellular, systemic and mucosal immune responses in an antigen-specific fashion. We therefore propose to 1) investigate this further with readily available SIV dead, inactivated viral particles in the mouse to better define the immunological basis for our encouraging observations, and to define and optimize the best parameters to study ISS-SIV/HIV-based immunization in the macaque model; 2) characterize the immune response to ISS-based vaccine in an immune deficient mouse, which emulates AIDS patients; and 3) evaluate ISS-based HIV vaccines in the macaque for their ability to induce specific immune responses and to protect from lethal HIV/SIV challenge. We hope that the data generated in this study will help in the design of a protective vaccination strategy against HIV in humans.